Critical Process Steps and Process Parameters for Validation with Justification

9.0

Process steps – Sampling and Analysis Plan with Acceptance Criteria

10.0

Hold Time study

11.0

Revalidation

12.0

OOSs and Investigations

13.0

Validation Report

14.0

Reference Documents

15.0

List of Annexures / formats Attached

PROTOCOL APPROVAL SHEET

This is a specific protocol for Process Validation of uncoated modified release tablet of Gliclazide Modified Release 60 Tablets which is manufactured at solid oral manufacturing facility in Pharmaceutical company

This protocol has been approved by the following:

Prepared by:

Functional Area

Name

Designation

Signature

Date

Quality Assurance

Checked by:

Functional Area

Name

Designation

Signature

Date

Process Development

Quality Assurance

Approved by:

Functional Area

Name

Designation

Signature

Date

R&D

Production

Quality Control

Regulatory Affairs

Quality Assurance

Objective

To provide documented evidence with high degree of assurance that the manufacturing process is capable of producing the finished product consistently of required quality, meeting its predetermined specifications and quality attributes.

Scope

This concurrent process validation protocol is applicable to carry out the process validation for Gliclazide Modified Release 60 Tablets on three consecutive batches at formulation Plant of pharmaceutical company.

Composite Sample:A desired amount of sample shall be taken after collection of samples from different location in one sample bag.

Pre-requisites for Validation

Process Equipments

All equipments to be used for the manufacturing process are qualified as per IQ/OQ/PQ acceptance criteria. The following equipments are to be used for manufacturing of Gliclazide Modified Release 60 Tablets

S.No.

Equipment Name

Process Step& Area

Make

Equipment

ID No.

Capacity

Qualification

status(report no.)

1.

Vibro Sifter

Sifting

2.

Conta Blender

Mixing

3.

Roll – Compactor

Slugging

4.

Comminuting-Mill

Milling

5.

Compression M/C

Tablet Compression

6.

Blister Packing Machine

Packing

Equipments / Instruments used for In-process checks

The following calibrated equipments / Instruments are used for in-process checks.

S. No.

Equipment /Instrument Name

Equipment ID. No.

Calibration status

(kit-used for calibration)

1.

Analytical weighing Balance

2.

Friability Test Apparatus

3.

Hardness Tester

4.

Vernier Caliper

Following specifications and Standard Test Procedures are referred for carrying out testing of validation samples.

*SPECIFICATIONS No. *STP No.

In-process:

Finished Product -Release:

*Testing of samples is done as per current version of STP’s and GTP’s

Approved Raw Materials

The raw material used for manufacturing process are from approved vendors and all the Raw Materials are tested before manufacturing process to ensure that material are of the acceptable quality prior to their use in the manufacturing .

WEIGHING :Weighing of lubricated granules is done by using a calibrated balance and calculate the actual .

SAMPLING : Inform to IPQA Department through In-process Analytical Request to collect the sample of blended granules , IPQA personnel send the sample to Quality Control Department for testing as per In-process Specification.

After completion of sifting, the process of dry mixing is evaluated for Homogeneity of drugs through sampling of the mixed blend after 20 minutes at 5 rpm. Blending is done using Conta Blender. This process step is evaluated for adequate blending time assessment through the determination of blend uniformity analysis of samples collected from different locations. .Refer Annexure-02 for sampling plan and analytical data compilation and acceptance criteria.It can influence both the content uniformity & assay of product.

SLUGGING

Feed screw rate, Speed of rollers. For detail refer Annexure-01.

To record and evaluate the variability of critical process variables for process step of slugging to achieve granules size of desired properties.

After addition of sifted Magnesium Stearate,Talc to the granules; blending is done using Conta Blender. This process step is evaluated for adequate blending of the lubricant by sampling of the blended granules from different locations from the blender bin after 10 minutes of blending. The assessment is taken through the determination of blend uniformity analysis in samples collected from different locations. The blend to be monitored for Bulk Density & Tapped Density on the composite sample collected after 5 minutes to determine the flow properties of the blended granules. Sampling is done by using suitable sampling thief. Refer Annexure-03 for sampling plan and analytical data compilation and acceptance criteria.

Tablets are Compressed using 37 Station Double Rotary Compression Machine. This process is evaluated through sampling the compressed tablets from both sides (left & right) produced at different intervals (Start, Middle and towards the end of compression). Samples are checked for the determination of Description, Average Weight, Uniformity of Weight, Thickness, Length, Width, Hardness & Friability against the established specifications at IPQA Laboratory

Compressed tablets are subjected for the determination of Uniformity of dosage units (by content uniformity for total Gliclazide Ph.Eur & Drug release .

One composite sample is subjected for complete analysis as per the established

Sampling is done as per mentioned in Sampling plan. The process parameters are challenged in the three validation batches.

Process Step

Sampling and Analysis Plan with Acceptance Criteria

Dry Mixing

Refer Annexure-02

Lubrication

Refer Annexure-03

Compression

Refer annexure-04

Hold time Studies

Process Step

Hold Time Studies Sampling and Analysis Plan with Justification

BLENDING /

LUBRICATION

TABLET COMPRESSION

About 300 gms material from blended mass is kept under simulating conditions. The material is subjected to analysis for Assay of Gliclazide Ph.Eur. Related substances and LOD at 0 day, after 7th day & after 15th day. These samples are tested for Bulk Density, Tapped Density, Compressibility Index and Hausner Ratio to rule out the de-blending of the materials. Hold time Study shall be carried out in one batch only.

Samples are also subjected separately for microbiological testing at 0 day, 7th day and 15th day.

Description: White to off white, flowing granules. sampled after 7th day and 15th day are comparable with that of 0 hr (initial).

Assay: Each 430 mg of granules contain not less than 97.5% and not more than 102.5% (58.5 mg to 61.5 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg).

Related substances:

Single highest impurity : Not more than 0.75%

(specified RRT about 0.30)

Single highest unknown impurity : Not more than 0.3%

Total impurities : Not more than 1.0%

Loss on drying: Between 1.0% to 3.2% w/w, determined at 1050 C for 7 minutes.

Bulk Density, Tapped Density, Compressibility Index and Hausner Ratio: Results of the samples sampled after 7th day & 15th day should be comparable with that of 0 day (initial)

Microbial Limits:

Total aerobic microbial count: NMT 500 cfu/g.

Total combined molds and yeasts count: NMT 50 cfu/g.

Escherichia coli: should be absent

Salmonella species: should be absent

Pseudomonas aeruginosa: should be absent

Staphylococcus aureus: should be absent

After completion of compression about 200.0 gms of compressed tablets are kept under simulating conditions for carrying hold Time studies. The sampling is done at 0 day, after 7th day & after 15th day. The sample is evaluated for the tests like Description, Assay and Related substances. Hold Time studies shall be carried out in one batch only.

Samples shall be subjected separately for microbiological testing at 0 day, after 7th day & after 15th day.

Sampling Quantity = About 425.2 mg to 1275.6 mg for each location sample and about 5 gm for composite sample

Shape of the blender bin with sampling location from 01 to 11
Sampling is done in triplicate from each sampling location using suitable sampling Device
Shape of the blender bin with sampling location from 01 to 11
Sampling is done in triplicate from each sampling location using suitable sampling Device
Record the following:

Sampling Location

Sampled by

(Sign & Date)

Sampling Date & Time

14 min

15 min

16 min

1

2

3

4

5

6

7

8

9

10

11

Composite sample

STAGE: BLENDING

Analysis Plan & Analytical Data Compilation:

Determination of Blend uniformity analysis of samples as per STP for location samples and determination of assay, L.O.D on the composite sample.

60 tablets are collected from machine at START, MID and towards the END of the compression and given to QC for determination of Uniformity of dosage units (by content uniformity), Drug release as per STP No. Also the 100 tablets as COMPOSITE SAMPLE (collected at start, mid and end & then pooled) is subjected to analysis as per STP at QC.

Note: Samples to be collected for determination of In-process at IPQA laboratory as per SOP and recording shall be done accordingly.